Steroid regulatory element-binding

OS are able to regulate key enzymes in CHOL turnover at transcriptional and post-transcriptional levels (Wolf, 1999 Bjorkhem, 2000 Tall et al., 2002). CHOL biosynthesis and homeostasis are regulated by two transcriptional factors steroid regulatory element-binding proteins (SREBP)-1 and -2. These become activated by proteolysis when the CHOL... 

Cholesteryl esters that are internalized via the LDL receptor are hydrolyzed to produce cholesterol and an acyl chain. Cholesterol, in (urn, activates the enzyme acyl-CoA cholesterol acyl-transferase (ACAT) which re-esterifies cholesterol. In an apparently futile cycle, the cholesteryl esters are hydrolyzed by cholesteryl ester hydrolase. The cholesterol moiety has several fates it may leave the cell and bind to an acceptor such as high-density lipoprotein (HDL), it may be converted to steroid hormones, or it may be reesterified by ACAT. When the cellular cholesterol concentration falls, the activity of HMG-CoA reductase is increased, as is the number of LDL receptors, which results in an increase of cellular cholesterol, due both to de novo synthesis and to the uptake of cholesterol-rich lipoproteins in the circulation. An increase in cellular cholesterol results in the rapid decline in the mRNA levels for both HMG-CoA reductase and the LDL receptor. This coordinated regulation is brought about by the presence of an eight nucleotide sequence on the genes which code for both proteins this is termed the sterol regulatory element-1. 

The receptor protein (52 kDa) is a member of the steroid hormone receptor superfamily, which has a DNA-binding as well as ligand-binding domain. Another receptor, the retinoid X receptor is also involved, and after binding of the peroxisome proliferator, the two receptors form a heterodimer. This binds to a regulatory DNA sequence known as the peroxisome proliferator response element. The end result of the interaction between peroxisome proliferators and this system is that genes are switched on, leading to increases in synthesis (induction) of both microsomal and peroxisomal enzymes and possibly hyperplasia. 

Each steroid hormone diffuses across the plasma membrane of its target cell and binds to a specific cytosolic or nuclear receptor. These receptor-ligand complexes accumulate in the nucleus, dimerize, and bind to specific regulatory DIMA sequences (hormone-response elements) in association with coactivator proteins, thereby causing promoter activation and increased transcription of targeted genes. 

As with vitamin A, mast of the effects of vitamin D involve a nuclear receptor. The vitamin D receptor is a member of the steroid/thyroid hormone superfamily of receptors. When I a,2S-OHD binds to its receptor, the complex forms a hetcrodimer with an unoccupied RXR. This heterodimer subsequently binds to the regulatory regions on specific genes in target tissue. These regions are called vitamin D response elements (VDREs). The binding to VDREs can increase or decrease expression of genes. The proteins thus made carry out the functions of vitamin D. 

Steroid and nuclear receptors are differentiated by their mode of DNA binding. GR, PR, AR, and ER all bind as homodimers to inverted-repeat sequences separated by three nucleotides (nnn), although the ER DNA binding domain recognizes a DNA sequence that is shared by the nuclear receptors. Nuclear receptors bind predominantly as heterodimers with RXR to direct-repeat sequences separated by one to five nucleotides. Structural studies have shown that RXR binds to the 50 half-site of the response element, which may be important for ligand-dependent transcriptional regulatory activity of the heterodimeric... 

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